This invention relates to a method for increasing coronary flow. Particularly, the invention relates to a method for obtaining direct dilatation of the coronary arteries by administering a phospholamban inhibitor as the active compound. The present invention also relates to novel phospholamban inhibitors, pharmaceutical compositions containing these compounds and new intermediates. Novel phospholamban inhibitors are also useful in the treatment of heart failure and stunned myocardium.
Contraction of the muscle cell is controlled by the amount of free cytosolic calcium interacting with calmodulin in smooth muscle cells or with troponin C in cardiac and skeletal muscle cells. These calcium-activated proteins trigger a cascade of events leading to cell shortening and muscle contraction.
One of the most important enzymes which aids to terminate or prevent the muscle contraction is the Ca2+-ATPase located inside the cell in the sarcoplasmic reticulum (SR). This enzyme transfers cytosolic calcium against the concentration gradient into the intracellular calcium storages. The function of the SR Ca.sup.2+ -ATPase (SERCA) is controlled by a small protein called phospholamban. When phospholamban is unphosphorylated, it inhibits the SERCA. In contrast, when phosphorylated, phospholamban does not inhibit this calcium pump. The removal of the inhibitory effect of phospholamban is seen as a stimulation of the calcium uptake into the SR, since some of the SERCA molecules are all the time under the inhibitory control of phospholamban.
Phospholamban has been shown to have an important role in the cardiac muscle (Lindemann, J. P. et al., "Beta-adrenergic stimulation of phospholamban phosphorylation and Ca.sup.2+ -ATPase activity in guinea pig ventricles", J. Biol. Chem. 258:464-471, 1983) and in the slow skeletal muscles, whereas the fast skeletal muscle does not express phospholamban at all (Hoh, J. F. Y, "Muscle fiber types and function", Current Opinion in Rheumatology, 4:801-808, 1992). Moreover, phospholamban is expressed in mouse aorta (Lalli, J. et al., "Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle", Circ. Res. 80(4): 506-513, 1997) and thereby it is thought that phospholamban controls SERCA in peripheral vascular tissue.
Through its inhibitory effects on the SERCA present in the cardiac tissue phospholamban represses both the rates of relaxation and contraction in the mammalian heart. Therefore, a compound capable of relieving the inhibitory effects of phospholamban on cardiac SERCA, e.g. by interrupting phospholamban-SERCA interaction, would be useful in the treatment of heart failure.
Evidence was very recently given that PLB is present in aortic endothelial cells (Sutliff, R. L. et al., "Functional and biochemical evidence for modulation of endothelial cell function by phospholamban", FASEB Journal 12 (5):A957, 1998), where it modulates the activity of the isoform of SERCA present on the endoplasmic reticulum. It was also shown that a decreased activity of the endoplasmic reticulum calcium pumping in aortic endothelial cells is leading to defective endothelium-dependent relaxation of aortic vascular smooth muscle (Liu, L. H. et al., "Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca.sup.2+ signalling in mice lacking sarco(endo)plasmic reticulum CA.sup.2+ -ATPase isoform 3", J. Biol. Chem. 272(48):30538-30545, 1997).
There is no published evidence of the presence of phospholamban in the endothelial cells of coronary arteries.